Method and apparatus for the coating of substrates for pharmaceutical use

ABSTRACT

A method of coating a substrate includes applying an active coating material to the substrate to form an active coating layer. The active coating material comprises biologically active material and the active coating layer is removable from the substrate.

The present invention relates to methods of coating substrates, toapparatus for coating substrates and to coated substrates forpharmaceutical use. In particular, but not exclusively, the inventionrelates to the coating of pharmaceutical substrates to produce soliddosage forms.

It is to be understood that the term “solid dosage form” is to beinterpreted in a broad sense as covering a wide variety ofpharmaceutical products. Thus the term covers pharmaceutical products tobe taken orally, for example, pharmaceutical tablets of conventionalshape as well as capsules and spherules and tablets of unconventionalshape. The term also covers pharmaceutical products not taken orally,for example, a pessary, a bougie, a suppository or a patch forapplication to the skin. Also, where reference is made to“pharmaceutical substrate” it is to be understood that the term coversthe substrates of the solid dosage forms indicated above. The term“solid dosage form” does not, however, include pharmaceutical productssuch as small pellets and granules, for example small pellets which arefilled into capsule shells for administration and granules which arecompressed to form tablets; such pellets or granules are not themselveseach solid dosage forms but rather, when combined together in a capsuleor tablet, define in combination a solid dosage form.

It will be understood that the term “active material” and “activecomponent” used throughout the specification includes material which isbiologically active and will comprise one or a mixture of pharmaceuticalmaterials. The pharmaceutical materials include those materials whichare administered for the prevention and/or treatment of disease.

Active materials are conventionally administered in the form of tablets.

In a conventional method of producing a pharmaceutical tablet, a mixturecontaining the biologically active ingredient together with diluentssuch as lactose and other ingredients is mixed and portions of themixture are formed into discrete tablets by, for example, pressingsamples of the mixture.

A problem with the method of producing tablets described above is that,due to inhomogeneity of the mixture from which the tablet cores aremade, the amount of active ingredient in the resulting tablet coresvaries from one tablet to the next. While that is a problem for alltypes of tablet core produced in that way, it is a particularly seriousproblem when the amount of active ingredient in each core is low, forexample for active compounds of high activity. In that case a smallabsolute variation in the percentage amount of active ingredient in thecores corresponds to a significant variation in the dose contained ineach tablet which is clearly most undesirable.

In one known method, a coating solution containing active material isapplied to the surfaces of small beads using conventional spray coatingtechniques, for example by spraying the coating solution towards thebeads as they are tumbled in a revolving drum. The coated beads arefilled into capsule shells for administration. Such a method is notappropriate for use where accuracy in the amount of the active materialapplied to the cores is required because there is little control overthe amount of coating material applied to each core using that method.

Active components are often administered in tablet form. As indicatedabove, conventional tablets include a small amount of active componentand a large amount of diluent such as lactose so that the tablet is aconvenient size. The tablet is a convenient way for the active componentto be administered because each tablet contains a predetermined metereddose of the active material.

However, some patients find the taking of tablets difficult, for examplebecause of their size or because of the presence of the otheringredients in the tablet composition. Thus an alternative dosage formwould be desirable.

GB 1 561 100 describes the coating of a web with material containing anactive ingredient. The coated web is processed to internalize the activecoating by, for example, lamination and winding to provide a dosageform.

It is an object of the invention to overcome or mitigate one or more ofthe above mentioned disadvantages.

In accordance with the invention, there is provided a method of coatinga substrate, the method including the steps of applying an activecoating material to the substrate to form an active coating layer, theactive coating material comprising biologically active material, whereinthe active coating layer is removable from the substrate.

In accordance with the invention, the active material is applied as acoating to a substrate from which it can be removed.

In one alternative embodiment of the invention, the coating material isapplied directly onto a surface of the coating apparatus, the coatingformed in the process being removed from the apparatus as a wafercontaining the active material.

In a second alternative embodiment of the invention, the coatingmaterial is applied onto a substrate, the coating being removed from thesubstrate as a wafer, for example by a patient prior to theadministration of the material. The substrate may be, for example, asheet comprising plastics material, for example low adhesion plasticsmaterial.

The surface of the substrate may be precoated with one or more coatinglayers.

Preferably, the active coating material is applied electrostatically.There are various advantages in applying coating materialselectrostatically, for example, reduction in waste of coating material,improved coating efficiency and improved coating weight uniformity.

In one alternative of the invention, the active coating material isapplied in the form of a dry powder.

Advantageously, at least 90% by weight of the particles of the activecoating material have a particle size less than 200 μm.

Advantageously, at least 90% by weight of the particles of the activecoating material have a particle size between from 1 to 200 μm.Preferably, at least 90% by weight of the particles of the activecoating material have a particle size between from 1 μm to 100 μm. Theterm “particle size” refers to the equivalent particle diameter of theparticles and may be measured using, for example, laser lightdiffraction. The particle size of the powder is an important factor inpowder coating techniques. If the particles of the powder are verysmall, the powder will often be too cohesive for successful powderapplication using many powder coating techniques. However, largeparticles can be disadvantageous because they are often more difficultto coat onto a surface and, if the coating material is to be fused afterapplication to the surface, longer fusing times may be required, leadingto increased risk of damage to the substrate and to the activecomponent.

Where reference is made to % by weight of particles, for example the %by weight of particles having a particular size, the particles will alsopreferably have that % by volume of particles of that size.

Alternatively, the coating material may be applied in the form of aliquid.

Advantageously, the active coating material further includes one or moreexcipients. The formulation will usually consist of the active componentand a mixture of excipients that will aid in the coating of thematerial. The formulation may also include other components, forexample, colorants and/or flavourings and/or agents to control the rateof release of the active component.

Advantageously, the substrate is conveyed through a region adjacent to asource of the active coating material. That allows the method to becontinuous.

In one advantageous embodiment of the invention, the method comprisessupporting the substrate adjacent to the source of the active coatingmaterial with a surface of the substrate maintained at such a differentelectric potential from that of the active coating material that theapplication of the electric potential causes the active coating materialto move from the source of the active coating material towards thesubstrate, a surface of the substrate becoming coated with the activecoating material.

Preferably, the substrate is supported from above and the powder movesfrom the source upwards towards a lower surface of the substrate.

Preferably, the substrate is charged when the substrate is adjacent thesource of the active coating material. Alternatively, or in addition,the source of active coating material may be charged.

The method may further include the step that after the active coatinglayer is applied the active coating material is treated to form anactive film coating secured to the surface of the substrate. Where thecoating material is in the form of a powder material, the treatmentadvantageously comprises a heating step, preferably by infra redradiation, but other forms of electromagnetic radiation may be used.Usually, the change in the coating upon heating will simply be aphysical change from a powder to a liquid and then, on cooling, to asolid coating, but there are other possibilities: for example, thepowder coating may comprise a polymer which is cured during thetreatment step, for example by irradiation with energy in the gamma,ultra violet or radio frequency bands, to form a cross-linked polymercoating.

The method may further include the step of applying a cover coatinglayer onto the active coating layer to form a cover coating layer suchthat the active coating layer is substantially completely covered by thecover coating layer.

The active coating material applied to the surface of the substratemight not be treated to form an active film coating. A cover coatinglayer applied subsequently over the active coating material could beused to seal the active coating on the surface of the substrate.

Where the coating material is in the form of a liquid, the treatmentadvantageously comprises drying the coating material with a heateralthough other methods could be used.

The coating material containing the active component is susceptible todamage at high temperatures and it is therefore particularly importantthat the temperature of treatment is not high. Advantageously, thetemperature of treatment is less than 250° C., preferably less than 200°C. and more preferably less than 150° C. Where the higher treatmenttemperatures are used, the duration of the treatment is advantageouslyshort to reduce the possibility of damage of the coating material.

Preferably, the cover coating material is applied electrostatically. Thecover coating material may be in the form of a powder. The cover coatingmaterial may also include active material. The active material in thecover coating may be the same as or different from the active materialin the active coating layer.

Advantageously, at least 90% by weight of the particles of the covercoating material have a particle size between from 1 to 200 μm.

Preferably, the substrate is conveyed through a region adjacent to asource of the cover coating material.

In one advantageous embodiment of the invention, the method comprisessupporting the substrate adjacent to the source of the cover coatingmaterial with a surface of the substrate maintained at such a differentelectric potential from that of the cover coating material that theapplication of the electric potential causes the cover coating materialto move from the source of the cover coating material towards thesubstrate, a surface of the substrate becoming coated with the covercoating material.

Advantageously, the substrate is supported from above and the powdermoves from the source upwards towards a lower surface of the substrate.

Preferably, the substrate is charged when the substrate is adjacent tothe source of the cover coating material. Alternatively, or in addition,the source of cover coating material may be charged.

Advantageously, the method further includes the step that after thecover coating layer is applied the cover coating material is treated toform a film coating secured to the surface of the substrate. Thetreatment of the cover coating layer may be similar to that of theactive coating layer described above.

In an embodiment of the invention the active coating layer covers onlypart of a surface of the substrate. In that embodiment, the covercoating layer may cover only part of a surface of the substrate, oralternatively may cover the whole surface of the substrate.

The cover coating layer may be applied by depositing powder whichthereafter forms a layer over the active coating layer or by applying apreformed sheet or film over the active coating layer.

The method may further include the step of applying a further coatingmaterial to a surface of the substrate to form a further coating layer.The further coating material may include biologically active material,the further coating layer forming a further active coating layer and themethod may further include the step of applying a further cover coatingmaterial onto the further active coating layer to form a further covercoating layer such that the further active coating layer issubstantially completely covered by the further cover coating layer.

Thus substrates having two or more different active components may beproduced. The cover coating material covering the first active coatingmay be different from that covering the second active coating so thatthe rate of release of the first active component may be different fromthat of the second active component. Alternatively, the two activecomponents may be the same and the cover coatings may be the same ordifferent materials. One or more of the cover coating materials maycontain active material.

Advantageously, the method is continuous. In practice, there areconsiderable advantages in being able to operate the coating processcontinuously rather than as a batch process.

Advantageously, the active coating material is applied to a part of asurface of the substrate, the active coating layer forming a firstactive coated region on the surface of the substrate. Where, forexample, a plurality of coating layers are to be applied to eachsubstrate, each coating layer forms a coated region on a part of thesubstrate.

Thus the method may include the further step of applying a second activecoating layer onto a surface of the substrate, the second active coatinglayer forming a second active coated region on a surface of thesubstrate.

Preferably, the method further includes the step of applying a covercoating material onto the active coating layer to form a cover coatinglayer such that the active coating layer is substantially completelycovered by the cover coating layer and such that the cover coating layeris removable from the substrate. Depending on the nature of the covercoating material, the cover coating layer may be removable together withthe active coating layer or may be removable separately. The covercoating layer provides a cosmetic coating and may also protect theactive coating material. The cover coating material may also includeactive material which may be the same as or different from the activematerial of the active coating layer. The cover coating may comprise apreformed film or sheet of material which is applied over the activecoating.

Where more than one active coating layer is applied to the substrate,the method preferably further includes the step of applying a secondcover coating layer onto the second active coating layer to form asecond cover coating layer such that the second active coating layer issubstantially completely covered by the second cover coating layer, thesecond cover coating layer being substantially separate from the firstcover coating layer.

The invention also provides a method of coating a plurality of coatingregions onto the surface of a substrate, the method comprising the stepsof:

-   -   (a) applying active coating material to a surface of the        substrate to form a plurality of active coating regions on the        surface comprising active coating layers, the active coating        material including biologically active material    -   (b) applying cover coating material to a surface of the        substrate to form a plurality of cover coating regions, the        cover coating regions forming layers of cover coating material,        each active coating region being substantially completely        covered by a cover coating region,        such that each region of active coating and cover coating is        removable from the surface of the substrate.

Advantageously, the method further includes the step of removing thatactive coating layer from the substrate to form a wafer comprisingactive material. Each wafer may comprise a single dose of activecomponent. Alternatively, the wafer may be subsequently cut to formwafer portions, each wafer portion including substantially a dose ofactive material.

Where reference is made to the quantity of active coating material beingsubstantially equal to a dose of the active material, it will beunderstood that the quantity may be a fraction of the single standarddose, for example ½ or ⅓ of a single standard dose of the activematerial. It will be understood that the quantity of active materialwill depend on the active component used and the number of solid dosageforms to be taken by the patient for each dose. Where more than onelayer of the active coating material is to be applied to each substrate,the quantity of active component in each layer will be chosenaccordingly.

The invention also provides apparatus for coating a substrate accordingto a method as described above.

The first aspect of the invention also provides an apparatus for coatinga substrate, the apparatus comprising:

-   -   (a) a source of active coating material,    -   (b) support means for supporting a substrate adjacent to the        source of the active coating material such that the active        coating material forms an active coating layer on a surface of        the substrate.

Advantageously, the apparatus further comprises:

-   -   (c) a source of a cover coating material,    -   (d) means for conveying the substrate having the active coating        layer to a position adjacent to the source of cover coating        material such that the cover coating material forms a cover        coating layer which substantially completely covers the active        coating layer.

The apparatus advantageously includes means for applying the activecoating material and/or the cover coating material electrostatically. Asindicated above, the coating material may be applied in the form of adry powder or in the form of a liquid.

Advantageously, the substrate comprises a conveyor belt.

Advantageously the apparatus further includes means for applying acharge to the source of active coating material. The charge can beadjusted to change the amount of coating material applied to thesubstrate.

Advantageously, the apparatus further includes charging means forapplying a charge to the substrate. The charge may be applied using acorona charge wire adjacent to the substrate or by arranging a chargedplate adjacent to the substrate. The charged substrate attracts coatingmaterial from the source onto the surface of the substrate. Thus it ispossible to obtain a very thin uniform layer of coating material on thesubstrate surface.

Preferably, the source is arranged below the conveyor.

Also provided by the present invention is an apparatus for coating asubstrate, the apparatus comprising:

-   -   (a) a source of coating material    -   (b) means for moving the substrate relative to the source of        coating material,    -   (c) means for applying an active coating material onto a surface        of the substrate to form a plurality of active coating regions,    -   (d) means for applying a cover coating material onto the surface        of the substrate to form a plurality of cover coating regions        such that each active coating region is substantially completely        covered by a cover coating region,        the coating materials being applied such that the active coating        material is removable from the surface of the substrate.

The invention also provides a coated substrate comprising an activecoating layer on a surface of the substrate, the active coating layerincluding biologically active material and in which the active coatinglayer is removable from the surface of the coated substrate.

In one embodiment of the invention, each active coating layer comprisesa quantity of biologically active material which is substantially equalto one dose or, for example, one half dose of the biologically activematerial. It will be understood that the quantity of active componentwill depend on the active material used and the required dose.

Alternatively the active coating layer may subsequently be cut intosmall portions.

Preferably, the substrate further includes a cover coating layer on asurface of the substrate, the cover coating layer substantiallycompletely covering the active coating layer in which the cover coatinglayer is removable from the surface of the substrate. As indicatedabove, the cover coating layer may be removable separately from theactive coating layer.

The substrate may include a plurality of active coating layers formingactive coating regions on a surface of the substrate.

Preferably, each active coating region includes a cover coating regioncomprising a layer of cover coating material in which each activecoating region is substantially completely covered by a cover coatingregion.

In one alternative embodiment of the present invention, for examplewhere the active coating material is applied as a liquid, the activecoating material is applied as a metered dose to a surface of thesubstrate, to form an active coating layer on the surface.

Very accurate application of the coating material on each surface can beobtained.

This is to be contrasted with the known methods where coating materialis sprayed towards the cores. In that case the amount of coatingmaterial applied to each substrate depends on many factors all of whichwould require close control if accurate application is to be achieved.It will be understood that whilst reference is made to applying ametered dose, that should not be taken to imply that there isnecessarily any measurement of the amount of material applied. A meteredvolume of liquid may be applied to each substrate.

Advantageously, a predetermined number of droplets of active coatingmaterial are applied to the surface of the substrate. Thus where thedroplets are of the same size, the number of droplets applied to thesubstrate surface determines the amount of active material applied. Byaltering the number of droplets applied, the apparatus can easily beadapted to apply the required quantity of active material.

Advantageously the coating method is such that the coefficient ofvariation of the quantity applied to each substrate or region of thesubstrate is not more than 15%.

As indicated above, where the coating material includes active material,the accuracy and reproducibility of the application of the material tothe substrates is of particular importance. For known sprayingtechniques such as those described above, the coefficient of variationcan be 50% or more. Whilst that is acceptable where the coating is acosmetic coating, it is not acceptable where the coating contains activematerial. Preferably the coefficient of variation is not more than 10%,and most preferably 3% or less.

Advantageously, the active coating material is applied in the form ofindividual liquid droplets which are propelled from the supply directlytowards a surface of the substrate.

As indicated above, where the material is applied as a plurality ofindividual droplets, it is more simple to alter the dose of activematerial applied to the substrate by changing the number of dropletsapplied. Thus advantageously, the number of droplets applied iscontrollable.

An ink jet head may be used in the coating of the substrates with activecoating material. A conventional ink jet head, for example those usedfor ink jet printers, can be used to apply an easily controllable amountof material from the head onto a substrate.

In one embodiment of the invention, the area of the surface of thesubstrate covered by the active coating layer is less than 40% of thetotal surface area of the substrate. The area covered by the activecoating layer may be less than 25% of the total surface area of thesubstrate. The active coating may form a plurality of small coatedregions on the surface of the substrate.

Thus the active coating layer may cover only a part of the exposedsurface of the substrate.

Where the quantity of active material to be administered using eachsolid dose is small, as indicated above, it is advantageous for theproportion of active component in the active coating material to belarge.

By covering a smaller proportion of the surface of the substrate, asmaller amount of coating material may be used. Thus the proportion ofactive component in the coating material may be increased.

The active coating material may be applied to a plurality of individualregions of the surface of the substrate.

The invention also provides a method of coating a substrate, the methodcomprising applying an active coating material to a surface of thesubstrate to form an active coating layer, the active coating materialcomprising biologically active material, applying a cover coating overthe exposed surfaces of the active coating layer and dividing thesubstrate to form substrate portions, each substrate portion includingsubstantially one dose of the active material.

The invention also provides a pharmaceutical solid dosage formcomprising a substrate and an active coating layer covering less than25% of the surface area of the substrate the active coating layercomprising biologically active material.

The coating layer may be shaped, for example to form a pattern, apicture, symbols, letters or numerals.

The invention also provides a wafer for administration to a patient, thewafer comprising biologically active material and having a thickness ofless than 2 mm. Preferably the thickness is less than 1 mm.

The invention further provides an intermediate product for use inproducing a plurality of solid dosage forms, the intermediate productcomprising a substrate and an active coating layer deposited on thesubstrate, the amount of active coating material deposited on a givenarea of the substrate being controlled such that the product cansubsequently be divided into portions with each portion containing apredetermined amount of active coating material, each predeterminedamount being one dose of the active material.

In accordance with a further aspect of the invention, there is provideda method of coating a substrate, the method comprising applying anactive coating material to a surface of the substrate to form an activecoating layer, the active coating material comprising biologicallyactive material, applying a cover coating layer over the exposedsurfaces of the active coating layer and dividing the layered product toform layered portions, each layered portion including substantially onedose of the active material.

In accordance with the further aspect of the invention, the activecoating material can be such that it is not removed from the substrate.For example, the active material might be applied to an edible filmwhich can be administered orally.

It will be understood that the method of coating may further includefeatures of the method of the first aspect of the invention describedherein. Furthermore, it will be appreciated that the apparatus andcoating materials described in respect of the first aspect of theinvention could be used in the method in accordance with the furtheraspect of the invention, with minor modifications where necessary.

Embodiments of the invention will now be described by way of examplehaving reference to the drawings of which:

FIG. 1 shows schematically a side view of an apparatus for coating atablet core;

FIG. 2 shows schematically a side view of a part of the apparatus ofFIG. 1; and

FIG. 3 shows schematically a side view of an apparatus for coating asubstrate in accordance with the invention.

The apparatus shown in FIG. 1 is for coating both faces ofpharmaceutical tablet cores. The apparatus comprises an inclined tabletcore feed chute 1 leading to a first rotatable wheel 2 having circulardepressions 3 in its outer surface. The cores 4 are fed from the chute 1into the depressions 3 where they are held by suction by means of asuction line 5 in communication with the base of the depression 3 via anopening. The first drum is rotated in the direction shown by the arrowA. Adjacent to the outer surface of the wheel 2 downstream from the feedchute 1 is an active coating station 6 and a cover coating station 7.Downstream from the active coating station is an active coating fusingstation 8 at which the active coating is fused and downstream from thecover coating station 7 is a cover coating fusing station 9 at which thecover coating is fused. A cooling station (not shown) may be provideddownstream from each of the fusing stations 8, 9 where cool air isdirected at the core to cool the fused coating.

A second wheel 10 similar to the first wheel 2 is arranged adjacent tothe first wheel 2, the nip between the wheels being downstream of thefusing station 9. The second wheel 10 rotates in an opposite sense tothat of the first wheel 2 as shown by the arrow B. Arranged adjacent tothe outer edge of the second wheel 10 downstream from the nip of the twowheels are a second cover coating station 11 and a second fusing station12.

FIG. 2 shows the active coating device 6 in more detail. FIG. 2 shows aportion of the wheel 2 together with a core 4 in a depression 3 on thesurface of the wheel 2. As described below, the apparatus of FIG. 2 canbe used to form wafers of coating material in accordance with thepresent invention.

The active coating station 6 comprises a conveyor 13 arranged in a loopin a vertical plane so that the upper surface 14 faces the surface ofthe wheel and the cores 4 which pass the device 6 as the wheel rotates.The contour of the upper surface 14 of the conveyor 13 is chosen tomatch the contour of the outer surface of the wheel so that the distancebetween the core and the upper surface of the conveyor is unchanged asthe wheel rotates. The direction of rotation C of the conveyor 13 issuch that the direction of movement of the upper surface of the conveyoris opposite to that of the movement of the core over the upper surfaceof the conveyor. Alternatively, the direction of movement of the uppersurface of the conveyor and the core may be the same.

As shown in FIG. 2, a corona charge wire 15 and powder source 16 arearranged beneath the conveyor immediately below the lower surface 17 ofthe conveyor.

The corona charge wire 15 sprays charge onto the lower surface 17 of theconveyor. It will be appreciated that a different method could be usedto apply charge to the conveyor.

The powder source 16 uses an archimedes screw to form a small mound ofpowder beneath the lower surface of the conveyor. The source 16comprises a hopper 18 containing the powder including the biologicallyactive component, and an Archimedes screw 19 which in use passes throughthe powder material 20 in the hopper 18 and through a vertical barrel21. Thus, the powder material 20 is circulated from the lower regions ofthe hopper 18 to the top of the barrel 21 where a moving heap of powderis formed. The heap will be of substantially constant size and shape asexcess powder overflows from the top of the barrel 21 and is returned tothe hopper 18.

Stirrers 22 are provided in the hopper 18 to help to improve the flow ofthe powder and break up any agglomerates.

Thus a small moving heap of powder of substantially constant size andshape is formed beneath the lower surface of the conveyor 17.

It will be appreciated that a device other than the Archimedes screwcould be used to form the heap of powder.

The powder source 16 is located downstream from the charge sprayingdevice 15 and powder from the heap of powder is attracted to the surfaceof the charged conveyor 17 where it forms a thin, uniform layer which istransported to the upper surface 14 of the conveyor.

The tablet core 4 passing over the upper surface of the conveyor is heldat a different potential from that of the conveyor 13, either byearthing the core or applying a charge to the core, and powder on theconveyor moves from the conveyor to the exposed surfaces of the tabletcore 4 to form a powder coating.

The active coating station 6 is enclosed in a housing (not shown) toreduce the risk of powder loss of the active powder. In use the housinghas an opening above the upper surface of the conveyor 14 so that thetablet core 4 is exposed to the active powder coating material as itpasses the station 6.

It will be appreciated that the thickness of the powder layer formed onthe surface of the tablet core depends on several factors including theamount of charge sprayed onto the conveyor, the magnitude of the chargeapplied to the core, the size of the heap of powder produced, the sizeof the opening in the housing and the speed of the conveyor. Thosefactors will be varied to give the desired coating depending on the typeof powder and core used.

The composition of the active coating material used will of coursedepend on the active ingredient to be used and the amount of the coatingto be applied.

Active materials most suitable to be applied to the tablet include thosematerials having a high therapeutic activity, for example those wherethe usual prescribed dose is about 1 mg or less, and which have a goodstability to degradation due to heat where the coating materialcontaining active material is to be heated.

An active material which may be applied to a tablet core in accordancewith the invention is Diltiazem HCL.

The amount of active ingredient to be coated onto each core or othersubstrate will generally be small and the active ingredient will usuallybe diluted with one or more excipients. The excipients used will bechosen so that they aid the coating of the active material onto thecores by, for example improving the electrostatic properties of thepowder and its physical properties and aiding the formation of the fusedactive coating, for example the excipient may be a material which meltsat a low temperature to aid the formation of a film.

Where the active coating material is a powder, the particle size will bean important factor with regard to the transfer of the active coatingmaterial from the conveyor to the tablet core and to the subsequentfusing of the material. Usually a particle size range of 1 to 200 μmwill be used (at least 90% of the particles of the powder having a sizewithin that range).

One example of an active coating material is as follows: Xylitol 45% wtDiltiazem HCL (active) 45% wt TiO₂  9% wt Colloidal silica  1% wt

It is thought that in at least one embodiment of the invention, theactive composition will comprise three main components together withadditives.

The components may, for example, comprise the following

-   -   i) a continuous phase component, for example Xylitol or PEG        6000,    -   ii) the active component,    -   iii) a particle seed and/or charge modifying component, for        example TiO₂ or silica,    -   iv) a flow aid, for example colloidal silica or magnesium        stearate.

Each component may comprise one or more different materials.

The active coating material of the above example was in the form of apowder and had a particle size distribution such that at least 90% wt ofthe particles had a size in the range of from 5 to 25 μm.

It is often preferred that at least 90% by weight of the particles havea size in the range of from 1 to 45 μm. In one preferred embodiment 90%by weight of the particles have a size less than 70 μm, 50% by weighthave a size less than 40 μm and 10% by weight of the particles have asize less than 10 μm.

The active powder coating material may be produced using one or acombination of the following processing steps:

-   -   a) precipitation of two or more of the components to form        composite particles    -   b) spray drying of two or more of the components to form        composite particles    -   c) granulation    -   d) extrusion    -   e) micronisation.

For example, all of the components of the composition may beco-micronised to give a powder material having the desired particlesize.

An example of a powder cover coating material is as is follows: 39.75%Eudragit RS (ammonio- methacrylate copolymer) 39.75% Klucel (hydroxypropyl cellulose)  15.0% Titanium dioxide  5.0% Aluminium lake  0.5%Aerosil 200 (colloidal silicon dioxide)

The cover coating material was prepared by the following method:

-   -   a) A sample containing the % wt of components listed above was        premixed in a high shear mixer. Water was added to the mixture        in a high shear mixer for a few minutes to give a granulated        mixture which was dried in a fluid bed drier at a temperature of        about 45° C. for 20 to 30 minutes to give a material having a        moisture content (measured as loss on drying) below 3% by        weight. The material was impact milled and then micronised using        a fluid energy mill to a powder containing particles having a        size distribution such that 50% by volume of particles were of a        size less than 20 μm.

The cover coating material will usually include percent by weight.

Powder from the powder source is attracted to the surface of the chargedconveyor where it forms a thin, uniform layer of powder on a part of theouter surface of the conveyor belt. A heater is positioned downstream ofthe powder source and the heater fuses the powder material on theconveyor surface to form a fused film coating on the surface. The filmcoating is conveyed on the conveyor to a region where it is removed as athin strip of film.

A cooling station may be positioned downstream of the heater to cool thefilm coating. The film strip removed from the conveyor may be passed toa cutting station where it is divided into portions, each of which maycontain a dose of active material.

In an alternative embodiment of the invention, powder material isdeposited onto a tape, preferably of plastics material.

In a further embodiment of the invention, the active coating is appliedas a liquid. A head for applying the liquid is positioned such that theoutlet or outlets of the head is less than 1 mm from the surface towhich the material is to be applied.

The head may be an ink jet printer head, for example an adapted Compact200 head manufactured by Alphadot Limited. That head has 5 outletsspread over an area of about 10 mm and can be used to direct liquidcoating material towards the exposed surfaces of the substrate.

The liquid coating material comprises the active component and asolvent, preferably water, and an excipient, for example PEG, to aid infilm forming. Preferably the solids content of the liquid coatingmaterial is very low, advantageously there would be substantially nosolids content and advantageously the active material is fully dissolvedin the solvent.

While it is envisaged that where the active layer is applied using anink jet printer head, the active components to control the dissolutionrate of the cover coating to give controlled release of the activematerial in the active coating layer. Where more than one active coatingis applied to each tablet or substrate, the release of each activecoating can be different where different materials are used for thecover coating over each of those active coatings.

Where one or more of the coatings are applied as liquid coatings, asuitable liquid coating device would be used at the active coatingstation 6 and/or the cover coating station 7 and the fusing device wouldbe replaced by, for example a drying device to dry the liquid coating,if necessary.

In an embodiment of the invention an apparatus similar to that shown inFIG. 2 is used to form wafers of coating material.

The apparatus comprises a conveyor belt of chemically inert materialhaving a Teflon (RTM) coating. A corona charge wire is arrangedimmediately below the lower surface of the conveyor and sprays chargeonto the lower surface. A powder source similar to that shown in FIG. 2is also arranged beneath the lower surface of the conveyor downstream ofthe corona wire. The powder material in the powder source contains anactive component and may have similar composition to the active powderdescribed above. Preferably a higher proportion of film-formingcomponents are added to the powder, for example hydroxypropylcellulose(HPC).

An example of an active coating material is as follows: Eudragit RS 23%Diltiazem HCL (active) 40% HPC 25% TiO₂ 7% PEG 4000 5%

The amounts of the components are expressed as material might be applieddirectly to a substrate from which it can be removed, it is thoughtthat, in particular where the active material is to be peelable from thesubstrate in the form of a wafer, the active material would be appliedto a base layer which is removable from the substrate.

For example, a first base coating layer would be applied to a substrateusing the apparatus shown in FIG. 2. Where the base coating material isapplied to the substrate in the form of a powder material, the basecoating would usually be fused to form the base coating layer. The basecoating layer would be peelable from the substrate. One or more regionsof active coating material would be applied to the base coating layer,for example using an ink jet printer head.

A cover coating would be applied over the active coating material. Wherethe cover coating is in the form of a powder, the cover coating wouldusually be fused to form the cover coating layer. The material would beremoved from the substrate in the form of a three-layer wafer in whichthe active material was sandwiched between two layers. The wafer maysubsequently be divided into smaller portions.

In a further embodiment of the invention, the active coating material isapplied to a substrate using an ultrasonic spray head. The ultrasonicspray head forms a cloud of liquid droplets which are chargedelectrostatically. A charge may be imparted on the droplets, forexample, by applying a high voltage to the ultrasonic spray head. Thecharged droplets become attracted to the substrate which is at apotential difference from the droplets.

Examples of active liquid coating materials which may be used are asfollows a) Sodium citrate 0.02 Chlorpheniramine maleate 2.48 Propyleneglycol 4.00 Water 18.50 Ethanol 75.00 b) Sodium citrate 0.02Chlorpheniramine maleate 2.00 Methocel E15 1.00 Lactose B.P. 6.00 PEG4000 1.00 Water 89.98

The amounts given above represent percentage by weight of eachcomponent.

The apparatus may include heating means (not shown) for drying theapplied coating material. However, where the liquid coating material issuch that the solvent evaporates quickly, the heater may not berequired. It will be appreciated that where the heater is used thetemperature required to dry the active coating will be significantlylower than the temperature required to fuse powder coating material asdescribed above.

FIG. 3 shows a further embodiment of the invention.

FIG. 3 shows a schematic view of an alternative arrangement of theapparatus for producing wafers including active material.

The apparatus is similar in operation to that described above in respectof FIG. 2 and comprises a stainless steel conveyor belt 31 (which may becoated with PTFE on its external surface) mounted for rotation on threerollers 34, 36. A powder hopper 32 is arranged below the conveyor 31 andwafer forming powder material is loaded into the hopper. The hopper isarranged to produce a recirculating powder bed either by fluidising thepowder in the hopper with dry air or by using an auger feed screwarrangement in the hopper and vibrating the powder in the hopper.

The hopper 32 is charged to from 0.5 to 10 kV either positively ornegatively depending on the wafer forming powder composition to be used.For the two compositions given below, the hopper would be chargednegatively.

A plate 33 is arranged above the portion of the conveyor belt 31 whichis adjacent to the hopper 32. The plate may be a stainless steel plateand is charged to a potential difference from that of the hopper 32. Theplate will normally be charged to the opposite sign to that of thehopper. The charge on the plate 33 may be from 0.1 to 10 kV depending onthe powder composition used and the thickness of the wafer to be formed.

The thickness of the layer formed on the surface of the belt willusually be from 0.5 to 3 mm. The charge applied to the hopper and to theplate 33, and the speed of the belt will be chosen to give the desiredthickness.

The powder composition is attracted to the conveyor belt 31 and adheresto the exterior surface of the belt to form a powder layer. The size ofthe hopper will usually be chosen so that the whole width of theconveyor belt is coated with powder. It is envisaged, however, that thepowder might coat less than the whole width of the conveyor belt 31.Also, the hopper 32 may comprise a group of several hoppers each forsupplying the same or different powder compositions to the conveyor belt31. Thus the wafer produced using the apparatus may be a composite waferin that it includes portions having different compositions. For example,the wafer might comprise a first layer including active material and asecond coating layer including no active material.

As indicated above, the wafer might comprise a first layer including noactive material, a second layer including active material and a thirdlayer including no active material. That arrangement is particularlypreferred because the active material is sandwiched between two outerlayers which help to protect the active material from mechanical orchemical damage.

Such a wafer may be formed by applying a coating layer to a substrate,applying the active material to the coating layer to form an activelayer and subsequently applying a cover coating layer over the activelayer. The first coating layer is removable from the substrate so that athree-layer wafer is formed.

Where reference is made herein to the active material being applied to asubstrate and being removable from a substrate, it will be understoodthat that includes the case in which the active material is applied to acoating layer which has previously been applied to the substrate, theactive coating layer being removable from the substrate together withthe coating layer.

The coated portion of the conveyor belt travels from the region of thehopper to the heated roller 34. The heated roller 34 is heated toslightly above the melting point of the powder composition on thesurface of the conveyor belt. As the conveyor belt moves around theheated roller 34, the powder composition on the outer surface of theconveyor belt melts and forms a fused coating on the surface of thebelt.

A chilled roller 35 is arranged above the conveyor belt 31 downstreamfrom the heated roller 34. The fused coating layer on the surface of theconveyor belt passes under the chilled roller 35 which smoothes theupper surface of the coating layer and cools the coating so that itsolidifies to form a wafer on the exterior surface of the conveyor belt.It will be appreciated that other methods could be used to cool andsmooth the coating layer, for example cool air jets arranged above theconveyor belt downstream from the heated roller 34.

The solidified wafer is transported on the conveyor belt 31 to thedoctor blade 37 where the wafer is peeled from the surface of the belt.The conveyor belt continues around the guide rollers 36 and a furthercoating is deposited onto the conveyor belt as powder material movesfrom the hopper to the belt as described above. Thus the apparatus canbe used to produce a continuous wafer.

It is thought that the width of the conveyor belt would usually be up to50 cm. The material may be applied across the whole width of theconveyor belt. Alternatively, the material might be applied as severalbands of material across the belt, the material being supplied fromseveral separate hoppers arranged below the belt.

The wafer peeled from the conveyor passes to a cutter 38 which may be arotary knife wafer chopper where the wafer is cut into uniform pieces.The cut wafer portions may be of any shape or size but will usuallycontain one dose of the active material present in the wafer. It will beappreciated that while circular or eliptical shaped wafer portions maybe preferred from an aesthetic point of view, such shapes would lead togreater wastage of wafer material than, for example, rectangular-shapedwafer portions.

The pieces are then passed to a packaging station 39 where they arepackaged using conventional methods to form, for example, blister packsor plasters for use as a patch on the skin.

Examples of suitable coating compositions are given above. Particularlysuitable powder compositions for use with the apparatus are as follows:Composition 1 Diltiazem HCl (active)   50% Eudragit RSPO Type C 47.5%(ammoniomethacrylate copolymer) Titanium dioxide   2% Sunset yellowpigment  0.5%

The % given are % by weight. The components were mixed and the mixturewas extruded and micronised to give a powder having a narrow particlesize distribution below 150 μm. For example, the particle sizedistribution may be as follows:

-   -   10% by weight less that 20 μm    -   50% by weight less than 50 μm

90% by weight less than 90 μm. Composition 2 Diltiazem HCl 40%Polyethylene glycol 6000 30% Xylitol 20% Titanium dioxide 10%

The components were wet granulated together, milled and sieved to form apowder having a narrow particle size distribution between 75 μm and 20μm.

It will be understood that other compositions containing active materialcould be used. The composition will usually include from 1% to 90% byweight of active material based on the weight of the composition. Theremainder of the formulation will usually comprise a polymeric matrix ofbinder material, for example Eudragit E100, gelatine, PVA, PVP-PVA, PEG,lactitol, polypropylene. The compositions may additionally includeplasticisers, opacifiers, disintegrants, detacifiers and/or pigments.

The apparatus described above may be modified so that the powdercomposition is deposited on a tape of material which is fed around theapparatus on the exterior surface of the conveyor, the tape having awafer coating being removed from the apparatus. The tape may beinedible, in which case the coating material may be removed from thetape on administration, where the active material is to be administeredorally. Alternatively, the tape may be used, for example, as a patch.Where the tape is edible, the active material may be administeredwithout removal from the tape, for example the tape and wafer portionmay be swallowed together.

Furthermore, as indicated above, the coating composition may be appliedto the substrate using a different method to that described above. Forexample, the coating material may be applied in the form of a liquidusing a head similar to that used in ink-jet printing. Alternatively,the coating material may be applied in the form of a liquid using anultrasonic spray head. Dots of coating composition would be applied toregions of the substrate using the head.

1. A method of coating a substrate, the method including the steps ofapplying an active coating material to the substrate to form an activecoating layer, the active coating material comprising biologicallyactive material, wherein the active coating layer is removable from thesubstrate.
 2. A method according to claim 1, wherein the active coatingmaterial is applied electrostatically.
 3. A method according to claim 1,wherein the active coating material is applied in the form of a drypowder.
 4. A method according to claim 3, wherein at least 90% by weightof the particles of the active coating material have a particle sizebetween from 1 to 200 μm.
 5. A method according to claim 1, wherein theactive coating material further includes one or more excipients.
 6. Amethod according to claim 1, wherein the substrate is conveyed through aregion adjacent to a source of the active coating material.
 7. A methodaccording to claim 6, wherein the method comprises supporting thesubstrate adjacent to the source of the active coating material with asurface of the substrate maintained at such a different electricpotential from that of the active coating material that the applicationof the electric potential causes the active coating material to movefrom the source of the active coating material towards the substrate, asurface of the substrate becoming coated with the active coatingmaterial.
 8. A method according to claim 6, wherein the substrate issupported from above and the powder moves from the source upwardstowards a lower surface of the substrate.
 9. A method according to claim6, wherein the substrate is charged when the substrate is adjacent tothe source of the active coating material.
 10. A method according toclaim 6, wherein the source of active coating material is charged.
 11. Amethod according to claim 1, wherein the method further includes thestep that after the active coating layer is applied the active coatingmaterial is treated to form an active film coating secured to thesurface of the substrate.
 12. A method according to claim 1, wherein themethod further includes the step of applying a cover coating layer ontothe active coating layer to form a cover coating layer such that theactive coating layer is substantially completely covered by the covercoating layer.
 13. A method according to claim 12, wherein the covercoating layer is removable from the substrate.
 14. A method according toclaim 1, wherein the active coating material is applied to a part of asurface of the substrate, the active coating layer forming a firstactive coated region on the surface of the substrate.
 15. A methodaccording to claim 1, wherein the method includes the further step ofapplying a second active coating layer onto a surface of the substrate,the second active coating layer forming a second active coating regionon a surface of the substrate.
 16. A method according to claim 15,wherein the method further includes the step of applying a second covercoating layer onto the second active coating layer to form a secondcover coating layer such that the second active coating layer issubstantially completely covered by the second cover coating layer, thesecond cover coating layer being substantially separate from the firstcover coating layer.
 17. A method of coating a plurality of coatingregions onto the surface of a substrate, the method comprising the stepsof: (a) applying active coating material to a surface of the substrateto form a plurality of active coating regions on the surface comprisingactive coating layers, the active coating material includingbiologically active material (b) applying cover coating material to asurface of the substrate to form a plurality of cover coating regions,the cover coating regions forming layers of cover coating material, eachactive coating region being substantially completely covered by a covercoating region, such that each region of active coating and covercoating is removable from the surface of the substrate.
 18. A methodaccording to claim 1, the method further including the step of removingthe active coating layer from the substrate to form a wafer comprisingactive material.
 19. A method according to claim 18, wherein the waferis cut to form wafer portions, each wafer portion includingsubstantially a dose of the active material.
 20. Apparatus for coating apharmaceutical substrate according to a method as claimed in claim 1.21. An apparatus for coating a substrate, the apparatus comprising: (a)a source of active coating material, (b) support means for supporting asubstrate adjacent to the source of the active coating material suchthat the active coating material forms an active coating layer on thesurface of the substrate.
 22. An apparatus according to claim 21,further comprising: (c) a source of a cover coating material, (d) meansfor conveying the substrate having the active coating layer to aposition adjacent to the source of cover coating material such that thecover coating material forms a cover coating layer which substantiallycompletely covers the active coating layer.
 23. An apparatus accordingto claim 21, wherein the substrate comprises a conveyor belt.
 24. Anapparatus according to claim 21, further including means for applying acharge to the source of active coating material.
 25. An apparatusaccording to claim 21, wherein the apparatus further includes means forapplying a charge to the substrate.
 26. An apparatus according to claim21, wherein the source is arranged below the substrate.
 27. An apparatusfor coating a substrate, the apparatus comprising: (a) a source ofactive coating material (b) means for moving the substrate relative tothe source of coating material, (c) means for applying an active coatingmaterial onto a surface of the substrate to form a plurality of activecoating regions (d) means for applying a cover coating material onto thesurface of the substrate to form a plurality of cover coating regionssuch that each active coating region is substantially completely coveredby a cover coating region, the coating materials being applied such thatthe active coating material is removable from the surface of thesubstrate.
 28. A coated substrate comprising an active coating layer ona surface of the substrate, the active coating layer includingbiologically active material and in which the active coating layer isremovable from the surface of the coated substrate.
 29. A coatedsubstrate according to claim 28, the substrate further including a covercoating layer on a surface of the substrate, the cover coating layersubstantially completely covering the active coating layer in which thecover coating layer is removable from the surface of the substrate. 30.A coated substrate according to claim 28, wherein the substrate includesa plurality of active coating layers forming active coating regions on asurface of the substrate.
 31. A coated substrate according to claim 30,wherein each active coating region includes a cover coating regioncomprising a layer of cover coating material in which each activecoating region is substantially completely covered by a cover coatingregion.
 32. A coated substrate when made according to a method asclaimed in claim
 1. 33. An intermediate product for use in producing aplurality of solid dosage forms, the intermediate product comprising asubstrate and an active coating layer deposited on the substrate, theamount of active coating material deposited on a given area of thesubstrate being controlled such that the product can subsequently bedivided into portions with each portion containing a predeterminedamount of active coating material, each predetermined amount being onedose of the active material.
 34. A wafer for administration to apatient, the wafer comprising biologically active material and having athickness of less than 2 mm.
 35. A wafer produced by a method accordingto claim
 18. 36. A method of coating a substrate, the method comprisingapplying an active coating material to a surface of the substrate toform an active coating layer, the active coating material comprisingbiologically active material, applying a cover coating layer over theexposed surfaces of the active coating layer and dividing the layeredproduct to form layered portions, each layered portion includingsubstantially one dose of the active material.